A genome-wide RNAi screen reveals multiple regulators of caspase activation

Yi, Caroline H.; Sogah, Dodzie Kwame; Boyce, Michael; Degterev, Alexei; Christofferson, Dana E.; Yuan, Junying

doi:10.1083/jcb.200708090

Cited by 74 publications

(77 citation statements)

References 31 publications

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“…This is probably a well-conserved phenomenon across evolution. Yuan and colleagues performed a genome-wide RNAi screen to identify genes that regulate caspase activation in Drosophila (Yi et al, 2007), and they found that many of the genes that regulated apoptosis were genes involved in metabolism; from carbohydrate metabolism to fatty acid synthesis.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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“…This may reflect that inhibition of Drp1 activity is itself lethal or damaging to mammalian cells and/or that Drp1 is only indirectly connected to the activity of Bax and Bak that more centrally mediates programmed cell death. Drp1 impact on Mfn1/2, OPA1, or even Miro-1, an OMM GTPase recently found to mediate caspase activation in Drosophila (Yi et al 2007), may be the key. If death stimuli are so great that Bcl-xL only partially protects cells, Drp1 inhibition may have little effect on cell viability even when an inhibition of cytochrome c release is apparent (Parone et al 2006).…”

Section: Post-translational Modification Of Drp1 Regulates Its Role Imentioning

confidence: 99%

Mitochondrial dynamics and apoptosis

Suen¹,

Norris²,

Youle³

2008

Genes Dev.

1,116

894

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In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.Apoptosis mediates the catabolism of eukaryotic cells that is crucial for metazoan development, adult tissue turnover, host defense pathways, and protection from cancer. All pathways of apoptosis converge upon the activation of caspases, proteases that orchestrate the efficient and noninflammatory demolition of cells. Two main pathways leading to caspase activation have been well characterized: the extrinsic route initiated by cell surface receptors leading directly to caspase 8 activation, and the intrinsic path that is regulated by mitochondria. The mitochondrial stage of apoptosis control is upstream of caspase activation and is mediated by the Bcl-2 family of proteins. One well understood role of mitochondria in caspase activation is to regulate the release of proteins from the space between the inner and outer mitochondrial membranes to the cytosol. When cytochrome c is released from mitochondria, it binds to APAF1 in the cytosol, activating the assembly of the apoptosome that activates caspase 9 (Bao and Shi 2007). Other proteins released from mitochondria, such as SMAC/Diablo, have less crucial accessory roles in caspase activation, perhaps most important in long-lived cells (Potts et al. 2005).Bcl-2 family proteins regulate the release of cytochrome c and other proteins through the outer mitochondrial membrane (OMM) (Adams and Cory 2007;Chipuk and Green 2008). Some members of the Bcl-2 family inhibit apoptosis, such as Bcl-2, Bcl-xL, and Mcl-1, whereas others, such as Bax and Bak, activate apoptosis. Bax and Bak actively induce cytochrome c release from mitochondria within cells and in cell-free systems, both of which are inhibited by anti-apoptotic Bcl-2 family members. As the anti-apoptotic Bcl-2 family members closely resemble the proapoptotic members in structure, they may function as dominant negative inhibitors by binding and inhibiting Bax and Bak. Another class of disparate proteins including Puma and Bim, called BH3-only proteins, shares a short motif with Bcl-2 family proteins and regulates their activity. One model posits that upon apoptosis initiation, BH3-only proteins are induced and then bind and inhibit anti-apoptotic Bcl-2 family proteins, allowing pro-apoptotic Bax and Bak to permeabilize the mitochondrial outer membrane releasing cytochrome c and other proteins to activa...

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“…In a genome-wide screen for genes required for apoptosis in Drosophila cells, multiple genes directly involved in cellular metabolism, such as genes encoding citrate synthase (CS) and 3-ketoacyl-acyl carrier protein synthase, were found to protect against apoptosis induced by the removal of DIAP1, which is a direct inhibitor of Drosophila caspases (Yi et al, 2007). Additional studies will be needed to identify the exact metabolic changes mediated by the downregulation of these 'housekeeping' genes that protect cells against apoptosis.…”

Section: Metabolic Regulation Of Caspase Activationmentioning

confidence: 99%